Abstract CT046: Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with <i>RAS</i> mutant solid tumors
Bibliographic record
Abstract
Abstract Background: Both MEK and CDK4/6 have been investigated as therapeutic targets in preclinical models of RAS mutant solid tumors. Multiple mechanisms contribute to synergism including the development of MAP kinase-dependence in RAS mutant cells exposed to CDK4/6 inhibition, leading to increased apoptosis, as well as enhanced induction of senescence with combinatorial vs. monotherapy treatment. We conducted a Phase 1 study of combined palbociclib and PD-0325901 in patients with RAS mutant solid tumors to assess safety, tolerability, and MTD, as well as pharmacokinetic parameters, preliminary efficacy and effects on mutant RAS allelic burden in plasma. Methods: Patients with RAS mutant solid tumors were enrolled utilizing a 3 + 3 design. Palbociclib and PD-0325901 were given orally once and twice daily, respectively for three of every four weeks. The maximum planned administered doses were 125 mg palbociclib daily and 8 mg PD-025901 twice daily. Pharmacokinetic parameters were measured on cycle 1 day 21 and plasma samples to measure RAS allelic burden were serially collected. Results: Twenty-five patients (17 with KRAS mutant NSCLC) who received at least one dose of each study drug were enrolled over 5 dose levels including (palbociclib/PD-0325901) 75/2, 75/4, 100/4, 125/4 and 125/8. The maximum administered dose of 125 mg palbociclib daily and 8 mg twice daily PD-0325901 was tolerable. One DLT of pneumonitis occurred at the 100/4 dose level. The most frequent (>10%) drug-related toxicities were leukopenia (72%), anemia (72%), thrombocytopenia (72%), neutropenia (64%), acneiform rash (64%), diarrhea (52%), fatigue (44%), lower extremity edema (32%), vomiting (28%), nausea (28%), oral mucositis (24%), increased AST (20%), increased creatinine (12%), epistaxis (12%), and blurred vision (12%). The median number of cycles completed was 3 (range: 1 - 28+). Across all patients, 1 patient (4%) with KRAS mutant NSCLC achieved partial response and 18 (72%) had stable disease as the best response. Eleven patients were progression-free > 3 months, and 6 were progression-free > 6 months, including 5 with KRAS mutant NSCLC, two of whom received prior immune checkpoint blockade. Among patients with KRAS mutant NSCLC, clinical benefit was seen among those with tumors harboring KRAS mutation alone, as well as those with tumors demonstrating concomitant loss of TP53 or CDKN2AB. A dose-dependent decrease in plasma RAS allelic burden was observed across dose levels. Conclusions: Administration of combined palbociclib and PD-0325901 was tolerable and produced promising progression-free survival among patients with KRAS mutant NSCLC. Additional dose levels utilizing continuous MEK inhibition are being evaluated. Citation Format: Geoffrey I. Shapiro, John Hilton, Leena Gandi, Nicole Chau, James Cleary, Andrew Wolanski, Adrienne Anderson, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Elizabeth Downey, Joseph Gibson, Solida Pruitt-Thompson, Alona Muzikansky, Suzanne Barry, Nora Feeney, Cloud Paweletz, Geoffrey Oxnard, Jeffrey Supko, Pasi Jänne, Kwok-Kin Wong, Bruce Johnson. Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with RAS mutant solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT046. doi:10.1158/1538-7445.AM2017-CT046
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".